The present invention relates to particulate products which may be prepared by using supercritical fluids. More particularly, the invention relates to novel crystalline forms of fluticasone propionate, which is S-fluoromethyl 6xcex1,9xcex1-difluoro-11xcex2-hydroxy-16xcex1-methyl-3-oxo-17xcex1-propionyloxyandrosta-1,4-diene-17xcex2-carbothiate. 
Fluticasone propionate is described and claimed in British Patent No. 2088877 (see Example 14 thereof). This compound has proven anti-inflammatory activity and is particularly useful for the treatment of respiratory disorders, particularly asthma. Fluticasone propionate has been obtained in a crystalline form, designated Form 1, by dissolving the crude product (obtained, e.g. as described in British Patent No. 2088877) in ethyl acetate and then recrystallising. Standard spray-drying techniques have also been shown to lead only to the known Form 1 of fluticasone propionate. According to the present invention, fluticasone propionate may be prepared in a new polymorphic form, designated Form 2. Form 2 may be characterised for example by its X-ray powder diffraction (XRPD) pattern (see infra).
The particulate products of the present invention are produced according to a supercritical fluid technique which we have developed.
The use of supercritical fluids (SCFs) and the properties thereof have been extensively documented, see for instance, J. W. Tom and P. G. Debendetti, xe2x80x9cParticle Formation with Supercritical Fluidsxe2x80x94A Reviewxe2x80x9d, J. Aerosol. Sci., 22 (5), 555-584 (1991). Briefly, a supercritical fluid can be defined as a fluid at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. Supercritical fluids have been of considerable interest, not least because of their unique properties. These characteristics include:
High diffusivity, low viscosity and low surface tension compared with liquids.
Large compressibility of supercritical fluids compared with the ideal gas implies large changes in fluid density for slight changes in pressure, which in turn results in highly controllable solvation power. Supercritical fluid densities typically range from 0.1-0.9 g/ml under normal working conditions. Thus, selective extraction with one supercritical fluid is possible.
Many supercritical fluids are normally gases under ambient conditions, which eliminates the evaporation/concentration step needed in conventional liquid extraction.
Most of the commonly used supercritical fluids create non-oxidising or non-degrading atmospheres for sensitive and thermolabile compounds, due to their inertness and moderate temperatures used in routine working conditions. Carbon dioxide is the most extensively used SCF due to its cheapness, non-toxicity, non-flammability and low critical temperature.
These characteristics have led to the development of several techniques of extraction and particle formation utilising supercritical fluids. In particular, two particle formation methods have been identified:
Rapid expansion of supercritical solution (RESS) (see, for instance, J. W. Tom and P. G. Debendetti, supra) involves the dissolution of the solute of interest in a supercritical fluid, followed by rapid expansion of the resulting supercritical solution to atmospheric pressure, resulting in the precipitation of solute particles.
Gas Anti Solvent (GAS) recrystallisation (P. M. Gallagher et al, Supercritical Fluid Science and Technology, ACS Symp. Ser. 406, 134 (1989)) is particularly useful in situations when the solvent of interest does not dissolve in, or has a very low solubility in, a supercritical fluid or a modified supercritical fluid. In this technique, the solute is dissolved in a conventional solvent. A supercritical fluid such as carbon dioxide is introduced into the solution, leading to a rapid expansion of its volume. As a result, the solvent power decreases dramatically over a short period of time, triggering the precipitation of the particles.
There is a need for techniques whereby a product may be obtained with consistent and controlled physical criteria, including control of particle size and shape, quality of the crystalline phase, chemical purity and enhanced handling and fluidising properties.
In addition, it would be advantageous to prepare micron-sized particles directly without the need to mill products to this size range. Such milling leads to associated problems such as increased static charge and enhanced particle cohesiveness, as well as reduced yield of product. It also leads to highly stressed particles, which stress may affect the particles, dissolution after administration.
Described in WO95/01324 is an apparatus for the formation of a particulate product in a controlled manner utilising a supercritical fluid particle formation system. The disclosure of WO95/01324 is incorporated herein by this reference. The apparatus comprises a particle formation vessel with means for controlling the temperature of said vessel and means for controlling the pressure of said vessel, together with a means for the co-introduction into said vessel of a supercritical fluid and a vehicle containing at least one substance in solution or suspension, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid.
As used herein, the term xe2x80x9csupercritical fluidxe2x80x9d means a fluid at or above its critical pressure (Pc) and critical temperature (Tc) simultaneously. In practice, the pressure of the fluid is likely to be in the range 1.01 Pc-7.0 Pc, and its temperature in the range 1.01 Tc-4.0 Tc.
The term xe2x80x9cvehiclexe2x80x9d means a fluid which dissolves a solid or solids, to form a solution, or which forms a suspension of a solid or solids which do not dissolve or have a low solubility in the fluid. The vehicle can be composed of one or more fluids.
As used herein, the term xe2x80x9csupercritical solutionxe2x80x9d means a supercritical fluid which has extracted and dissolved the vehicle.
The term xe2x80x9cdispersionxe2x80x9d means the formation of droplets of the vehicle containing at least one substance in solution or suspension.
The term xe2x80x9cparticulate productxe2x80x9d includes products in a single-component or multi-component (e.g. intimate mixtures of one component in a matrix of another) form.
It will be appreciated that, where necessary, the apparatus may additionally comprise a means for the collection of the particulate product, for example, a means for the retention of the product in the particle formation vessel, such as a filter, thus reducing loss of the product together with the resultant supercritical solution. An alternative means may involve a cyclone separating device.
The apparatus mentioned above and its use provide the opportunity for manufacturing dry particulate products with controlled particle size and shape by offering control over the working conditions, especially the pressure, utilising, for example, an automated back-pressure regulator such as model number 880-81 produced by Jasco Inc. Such an improved control eliminates pressure fluctuation across the particle formation vessel and ensures a more uniform dispersion of the vehicle (containing at least one substance in solution or suspension) by the supercritical fluid with narrow droplet size distribution during the particle formation process. There is little or no chance that the dispersed droplets will reunite to form larger droplets since the dispersion occurs by the action of the supercritical fluid which also ensures thorough mixing with the vehicle and rapidly removes the vehicle from the substance(s) of interest, leading to particle formation.
The simultaneous co-introduction of the vehicle containing at least one substance in solution or suspension and the supercritical fluid, according to the method described herein, allows a high degree of control of parameters such as temperature, pressure and flow rate, of both vehicle fluid and supercritical fluid, at the exact point when they come into contact with one another.
Further advantages for particles formed as described herein include control over the quality of the crystalline and polymorphic phases, since the particles will experience the same stable conditions of temperature and pressure when formed, as well as the potential of enhanced purity. This latter feature can be attributed to the high selectivity of supercritical fluids under different working conditions, enabling the extraction of one or more of the impurities from the vehicle containing the substance of interest.
The means for the co-introduction of the supercritical fluid and the vehicle into the particle formation vessel preferably allows for them to be introduced with concurrent directions of flow, and more preferably takes the form of a coaxial nozzle as described below. This ensures no contact between the formed particles and the vehicle fluid around the nozzle tip area. Such contact would reduce control of the final product size and shape. Extra control over the droplet size, in addition to that provided by nozzle design, is achieved by controlling the flow rates of the supercritical fluid and the vehicle fluid. At the same time, retaining the particles in the particles formation vessel eliminates the potential of contact with the vehicle fluid that might otherwise take place on depressurising the supercritical solution. Such contact would affect the shape and size, and potentially the yield, of the product.
Thus, in the apparatus described herein and in WO95/01324 the means for the co-introduction of the supercritical fluid and the vehicle (containing at least one substance in solution or suspension) into the particle formation vessel preferably comprises a nozzle the outlet end of which communicates with the interior of the vessel, the nozzle having coaxial passages which terminate adjacent to one another at the outlet end, at least one of the passages serving to carry a flow of the supercritical fluid, and at least one of the passages serving to carry a flow of the vehicle in which a substance is dissolved or suspended.
Preferably, the opening at the outlet end (tip) of the nozzle will have a diameter in the range of 0.05 to 2 mm, more preferably between 0.1 and 0.3 mm, typically about 0.2 mm. The angle of taper of the outlet end will depend on the desired velocity of the fluids introduced through the nozzle; an increase in the angle may be used, for instance, to increase the velocity of the supercritical fluid introduced through the nozzle and hence to increase the amount of physical contact between the supercritical fluid and the vehicle. Typically (although not necessarily) the angle of taper will be in the range of about 10xc2x0 to about 50xc2x0, preferably between about 20xc2x0 and about 40xc2x0, more preferably about 30xc2x0. The nozzle may be made of any appropriate material, for example stainless steel.
In one embodiment, the nozzle has two coaxial passages, an inner and an outer. In another, preferred, embodiment, the nozzle has three coaxial passages, an inner, an intermediate and an outer. This latter design allows greater versatility in use of the apparatus, since if necessary two vehicles may be introduced into the particle formation vessel with the supercritical fluid. Improved dispersion and finer particles can also be obtained if such a nozzle is used to introduce a flow of the vehicle sandwiched between an inner and an outer flow of the supercritical fluid, since this ensures that both sides of the vehicle are exposed to the supercritical fluid. It is, however, to be appreciated that the nozzle may have any appropriate number of coaxial passages.
The internal diameters of the coaxial passages may be chosen as appropriate for any particular use of the apparatus. Typically, the ratio of the internal diameters of the outer and the inner passages may be in the range of from 2 to 5, preferably between about 3 and 5. Where an intermediate passage is included, the ratio of the internal diameters of the outer and intermediate passages may be in the range of from 1 to 3, preferably between about 1.4 and 1.8.
Particular examples of such coaxial nozzles and their typical dimensions are illustrated in FIGS. 2A, 2B and 4 herein.
The temperature of the particle formation vessel may be maintained (preferably xc2x10.1xc2x0 C.) by means of a heating jacket or, more preferably, an oven. The pressure of the particle formation vessel is conveniently maintained (preferably xc2x12 bar) by means of a back-pressure regulator. It will be appreciated that such apparatus will be readily available from, for example, manufacturers of supercritical fluid extraction equipment, for instance, from Jasco Inc., Japan.
The invention provides a method for the formation of a particulate fluticasone propionate product which comprises the co-introduction of a supercritical fluid and a vehicle containing at least fluticasone propionate in solution or suspension into a particle formation vessel, the temperature and pressure in which are controlled, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid.
Dispersion and extraction will also typically occur substantially immediately on introduction of the fluids into the particle formation vessel. Co-introduction of the supercritical fluid and the vehicle containing at least fluticasone propionate in solution or suspension preferably is effected using a nozzle of coaxial design.
Suitably the particle formation vessel used is as described in WO95/01324.
Suitable chemicals for use as supercritical fluids include carbon dioxide, nitrous oxide, sulphur hexafluoride, xenon, ethylene, chlorotrifluoromethane, ethane and trifluoromethane. Particularly preferred is carbon dioxide.
The supercritical fluid may optionally contain one or more modifiers, for example, but not limited to, methanol, ethanol, ethyl acetate, acetone, acetonitrile or any mixture thereof. When used, the modifier preferably constitutes not more than 20%, and more particularly constitutes between 1 and 10%, of the supercritical fluid.
The term xe2x80x9cmodifierxe2x80x9d is well known to those persons skilled in the art. A modifier (or co-solvent) may be described as a chemical which, when added to a supercritical fluid, changes the intrinsic properties of the supercritical fluid in or around the critical point.
Regarding the choice of vehicle for the fluticasone propionate, where the fluticasone propionate is to be handled as a solution it should be soluble in the chosen vehicle, and the chosen vehicle should be soluble in the chosen supercritical fluid. The choice of a suitable combination of supercritical fluid, modifier (where desired) and vehicle for any desired product will be well within the capabilities of a person of ordinary skill in the art.
Suitable solvents may be, for example, methanol, ethanol, ethyl acetate, acetone, acetonitrile or any mixture thereof.
Control of parameters such as size, shape and crystal habit in the particulate product will be dependent upon the operating conditions used when carrying out the method of the invention. Variables include the flow rates of the supercritical fluid and/or the vehicle containing substance(s), the vehicle used to dissolve the substance(s), the concentration of the substance(s) in the vehicle, and the temperature and pressure inside the particle formation vessel.
It will also be appreciated that the precise conditions of operation of the present apparatus will be dependent upon the choice of supercritical fluid and whether or not modifiers are present.
Table 1 lists the critical pressure and temperatures for some selected fluids:
In practice, it may be preferable to maintain the pressure inside the particle formation vessel substantially in excess of the Pc (for instance, 100-300 bar for carbon dioxide) whilst the temperature is above the Tc (e.g. 35-75xc2x0 C. for carbon dioxide).
The flow rates of the supercritical fluid and/or the vehicle may also be controlled so as to achieve a desired particle size, shape and/or form. Although the flow ratio will be dependent on the desired characteristics of the fluticasone propionate, typically the ratio of the vehicle flow rate to the supercritical fluid flow rate will be between 0.001 and 0.1, preferably between 0.01 and 0.07, more preferably around 0.03.
The method described herein preferably additionally involves collecting the particulate product following its formation. It may also involve recovering the supercritical solution formed, separating the components of the solution and recycling one or more of those components for future use.
According to a preferred aspect of the present invention, there is provided the compound fluticasone propionate in an easily handled and easily fluidised crystalline form, with a controlled particle size and shape, and optionally also with a controlled morphology and level of agglomeration.
The invention also provides a new crystalline form of fluticasone propionate, designated Form 2 fluticasone propionate as described herein. The precise conditions under which Form 2 fluticasone propionate is formed may be empirically determined; herein (see Example 5) we give a number of examples of methods which have been found to be suitable in practice.
As mentioned above, control of parameters such as size, shape and crystal habit in the particulate product will be dependent upon the operating conditions used when carrying out the method of the invention. By appropriate adjustment of the variables of the process, the relative amounts of Forms 1 and 2 of fluticasone propionate produced with the apparatus described herein may be altered by the person skilled in the art. The experimental domains for each polymorphic form can be determined empirically for the particular apparatus employed.
Conventionally crystallised fluticasone propionate, even after micronisation (fluid milling), exists in a form with very poor flow characteristics, for example it is cohesive and statically charged, which results in difficulties in handling the drug substance in pharmaceutical formulation processes.
In another aspect of the present invention, there is provided fluticasone propionate in a form with a dynamic bulk density of less than 0.2 g cmxe2x88x923. In a preferred aspect of the present invention, there is provided fluticasone propionate in a form with a dynamic bulk density in the range between 0.05 and 0.17 g cmxe2x88x923, and, in particular, in the range between 0.05 and 0.08 g cmxe2x88x923.
The dynamic bulk density (W) is indicative of a substance""s fluidisability and is defined as:   W  =                              (                      P            -            A                    )                ⁢        C            100        +    A  
where P is the packed bulk density (g cmxe2x88x923), A is the aerated bulk density (g cmxe2x88x923) and C is the compressibility (%) where C is calculated by the equation:   C  =                    P        -        A            P        xc3x97    10  
Clearly, a low figure for W corresponds to a high degree of fluidisability.
When compared against conventionally crystallised fluticasone propionate, both before and after micronisation, fluticasone propionate of the present invention exhibits a significantly lower dynamic bulk density than the conventionally crystallised fluticasone propionate as illustrated in Table 7 (see Example 6 below).
It will be appreciated that in the case of an inhaled pharmaceutical, such as fluticasone propionate, it is particularly desirable to produce a drug substance which is readily fluidisable, thereby potentially improving its inhalation properties.
The fluticasone propionate of the present invention is observed to have improved handling and fluidising characteristics compared with conventionally crystallised fluticasone propionate.
Furthermore, the particle size and shape of provided fluticasone propionate of the present invention can be controlled as illustrated by the electronmicrographs herein.
Preferably, the fluticasone propionate of the present invention is within the particle size range suitable for pharmaceutical dosage forms to be delivered by inhalation or insufflation. A suitable particle size range for this use is 1 to 10 microns, preferably 1 to 5 microns. Particles generally have a uniform particle size distribution, as measured by a uniformity coefficient of from 1 to 100, typically 1 to 20 e.g. 5 to 20.
The particle size distribution of the fluticasone propionate according to the invention may be measured by conventional techniques, for example by laser diffraction, by the xe2x80x9cTwin Impingerxe2x80x9d analytical process or by the xe2x80x9cCascade Impactionxe2x80x9d analytical process. As used herein reference to the xe2x80x9cTwin Impingerxe2x80x9d assay means xe2x80x9cPreparations for Inhalation: Aerodynamic assessment of fine particles using apparatus Axe2x80x9d as defined in the British Pharmacopoeia 1993, Addendum 1996, pages A522-527 as applied to a dry powder inhalation formulation. As used herein reference to the xe2x80x9cCascade Impactionxe2x80x9d assay means xe2x80x9cPreparations for Inhalation: Aerodynamic assessment of fine particles using apparatus Dxe2x80x9d as defined in the British Pharmacopoeia 1993, Addendum 1996, page 527 as applied to a metered dose inhaler formulation. The preferred fluticasone propionate according to the invention of mean particle size between 1 and 10 microns has been found to have a respirable fraction of 14% or more by weight.
The fluticasone propionate of the present invention typically has a low cohesivity, for example of 0 to 20%, preferably 0 to 10% employing methods of measurement based on those described by R. L. Carr in Chemical Engineering 1965, 163-168.
The fluticasone propionate according to the invention may be used to prepare a pharmaceutical composition which may be presented for use in a conventional manner with the aid of a pharmaceutically acceptable carrier or excipient, optionally with supplementary medicinal agents. Preferred carriers include, for example, polymers e.g. starch and hydroxypropylcellulose, silicon dioxide, sorbitol, mannitol and lactose e.g. lactose monohydrate. The compositions may be in a form suitable for administration by inhalation or insufflation, or for oral, buccal, parenteral, topical (including nasal) or rectal administration. Administration by inhalation or insufflation is preferred.
In a preferred pharmaceutical composition according to the invention the fluticasone propionate and carrier are co-crystallised together using the process and apparatus described herein to form multicomponent particles comprising both fluticasone propionate and carrier. Such multicomponent particles represent a further aspect of the invention.
In a preferred aspect the invention provides a pharmaceutical composition in the form of a dry powder suitable for inhalation or insufflation which comprises fluticasone propionate according to the present invention and a suitable powder base such as lactose or starch, preferably lactose, as carrier. Especially preferred are compositions comprising fluticasone propionate and lactose in the form of multicomponent particles. The dry powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insufflator.
For administration by inhalation the fluticasone propionate made in accordance with the invention may be conveniently delivered in the form of an aerosol spray presentation from pressurised packs such as metered dose inhalers, with the use of a suitable propellant, such as dichlorodifluoromethane or preferably a fluorocarbon or hydrogen-containing fluorocarbon such as HFA134a (1,1,1,2-tetrafluoroethane), HFA227 (1,1,1,2,3,3,3-heptafluoro-n-propane) or mixtures thereof. Such aerosol spray presentations may include surfactants, e.g. oleic acid or lecithin; co-solvents, e.g. ethanol; or other excipients conventionally used in such formulations.
The formulations for administration by inhalation or insufflation are intended for administration on a prophylactic basis to humans suffering from allergic and/or inflammatory conditions of the nose, throat or lungs such as asthma and rhinitis, including hay fever. Aerosol formulations are made so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains from 20 to 1000 micrograms, preferably 25 to 150 micrograms of fluticasone propionate of the invention. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses each time. The overall daily dose with an aerosol will be within the range 100 micrograms to 10 mg, preferably 100 micrograms to 1.5 mg.